Scheuing Lisa, Chiu Chi-Tso, Liao Hsiao-Mei, Chuang De-Maw
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health Bethesda, MD, USA.
Front Neurosci. 2015 Jul 21;9:249. doi: 10.3389/fnins.2015.00249. eCollection 2015.
A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.
重度抑郁症是一种使人衰弱的精神障碍，是全球疾病负担的主要原因。现有的抗抑郁药物对大多数抑郁症患者并不适用，大型临床研究已证明其疗效有限且起效缓慢。越来越多的证据表明，低剂量氯胺酮具有快速且强效的抗抑郁作用，这为未来的抗抑郁药物提供了强大潜力。然而，氯胺酮有相当多的缺点，如具有滥用潜力、拟精神病作用以及增加大脑中的氧化应激，因此限制了其在临床上的广泛应用。为了开发更优质的抗抑郁药物，更好地理解氯胺酮的抗抑郁作用机制至关重要。最近的临床前研究表明，氯胺酮的抗抑郁机制涉及雷帕霉素哺乳动物靶点通路的激活以及随后前额叶皮质中的突触形成，还有糖原合酶激酶-3β（GSK-3β）的失活。辅助性的GSK-3β抑制剂，如锂盐，可以通过增强和延长氯胺酮的抗抑郁作用来提高其疗效。鉴于存在抑郁复发的可能性，除氯胺酮外使用锂盐是解决这一临床问题的一个有前景的方案。
